nACfiR upregulation by ciironic exposure to nicotine and ottier nicotinic drugs The Overall Progress Report and Overall Description sections provide the logic and background for the study of receptor upregulation by candidate drugs. Upregulation in 2 pathways related to nicotine addiction Cellular and circuit-level research on nAChRs is governed by the fact that only a handful of papers present believable eEPSCs, sEPSCs, or mEPSCs associated with nAChR activation by ACh in the brain. Investigators believe that most HS nicotinic receptors are on presynaptic terminals, where they control transmitter release (and therefore pose challenges for detailed study) (MacDermott et al., 1999). Many studies also reveal the presence of somatodendritic HS nAChRs (mostly a4B2* and a6*). Little or no evidence shows that these somatodendritic receptors respond to circulating or released ACh. But there is much evidence that these nAChRs do respond to nicotine with both activation and, in some cases, desensitization, primarily because nicotine is not hydrolyzed by acetylcholinesterase.